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      The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

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          Summary

          Immunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T‐cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate CD4 T‐cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include human immunodeficiency virus ( HIV), tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. CD4 T‐cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory CD4 T‐cells, we need to understand how memory CD4 T‐cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory CD4 T‐cells that are found in peripheral tissues (tissue resident memory T‐cells) and in the circulation (central and effector memory T‐cells). We discuss the generation of these cells, and the evidence that demonstrates how they provide immune protection in animal and human challenge models.

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          Most cited references59

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major.

            CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.
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              Recapitulating adult human immune traits in laboratory mice by normalizing environment

              Our current understanding of immunology was largely defined in laboratory mice because of experimental advantages including inbred homogeneity, tools for genetic manipulation, the ability to perform kinetic tissue analyses starting with the onset of disease, and tractable models. Comparably reductionist experiments are neither technically nor ethically possible in humans. Despite revealing many fundamental principals of immunology, there is growing concern that mice fail to capture relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside 1–8 . Laboratory mice live in abnormally hygienic “specific pathogen free” (SPF) barrier facilities. Here we show that the standard practice of laboratory mouse husbandry has profound effects on the immune system and that environmental changes result in better recapitulation of features of adult humans. Laboratory mice lack effector-differentiated and mucosally distributed memory T cells, which more closely resembles neonatal than adult humans. These cell populations were present in free-living barn populations of feral mice, pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting a role for environment. Consequences of altering mouse housing profoundly impacted the cellular composition of the innate and adaptive immune system and resulted in global changes in blood cell gene expression patterns that more closely aligned with immune signatures of adult humans rather than neonates, altered the mouse’s resistance to infection, and impacted T cell differentiation to a de novo viral infection. These data highlight the impact of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modeling immunological events in free-living organisms, including humans.

                Author and article information

                Contributors
                Megan.Macleod@glasgow.ac.uk
                Journal
                Immunology
                Immunology
                10.1111/(ISSN)1365-2567
                IMM
                Immunology
                John Wiley and Sons Inc. (Hoboken )
                0019-2805
                1365-2567
                17 April 2018
                August 2018
                17 April 2018
                : 154
                : 4 ( doiID: 10.1111/imm.2018.154.issue-4 )
                : 574-581
                Affiliations
                [ 1 ] Centre for Immunobiology Institute of Infection, Immunity and Inflammation University of Glasgow Glasgow UK
                [ 2 ] GLAZgo Discovery Centre Institute of Infection, Immunity and Inflammation University of Glasgow Glasgow UK
                Author notes
                [*] [* ] Correspondence: Megan K. L. MacLeod, Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University PlaceSGDB, Glasgow G12 8TA, UK. Email: Megan.Macleod@ 123456glasgow.ac.uk

                Senior author: Megan K.L. MacLeod

                Author information
                http://orcid.org/0000-0003-1843-8580
                Article
                IMM12929
                10.1111/imm.12929
                6050220
                29570776
                911e09c5-3bc9-4d09-b58d-e5f1cb5a3f7e
                © 2018 The Authors. Immunology Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 February 2018
                : 02 March 2018
                : 06 March 2018
                Page count
                Figures: 1, Tables: 0, Pages: 8, Words: 7786
                Funding
                Funded by: AstraZeneca
                Funded by: DTP‐MRC
                Award ID: MR/J50032X/1
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                imm12929
                August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:17.07.2018

                Immunology
                cd4 t cell,cytokine,infection,memory,vaccine
                Immunology
                cd4 t cell, cytokine, infection, memory, vaccine

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